Coronary artery disease (CAD) is one of the most important leading causes of morbidity and mortality worldwide. Few studies have been carried out in the Saudi population regarding the association of rs10757278 polymorphism with CAD. This study aimed to investigate the association of the rs10757278 polymorphism with CAD in Saudi population. We recruited 437 patients with CAD and 251 cross-matched healthy controls and performed polymorphism genotyping for rs10757278 using a polymerase chain reaction followed by a restriction fragment length polymorphism analysis. Results: The G allele (OR-1.44; 95% CI: 1.15–1.80; p=0.001), as GG (OR-2.13; 95% CI: 1.35–3.36; p=0.0009), in the dominant (OR-1.47; 95% CI: 1.03–2.10; p=0.03) and recessive mode (OR-1.84; 95% CI: 1.26–2.70; p=0.001) of inheritance showed a high-risk association. A disease stratified risk analysis was conducted and comparisons were made using an ANOVA analysis. Diabetes showed a risk association (p=0.001). However, a regression analysis confirmed that for the CAD cases, there was an association between the GG genotype and diabetes (p=0.005). The results of this study suggest that the polymorphism rs10757278 is related to a high risk of CAD in a Saudi population.